D1 Antagonists

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John D. Salamone - One of the best experts on this subject based on the ideXlab platform.

  • Differential effects of selective adenosine Antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism.
    Neuroscience, 2010
    Co-Authors: Eric J. Nunes, Patrick A. Randall, Jessica L. Santerre, Ashby B. Given, Thomas N. Sager, Mercè Correa, John D. Salamone
    Abstract:

    Abstract Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A2A Antagonists can reverse the effects of DA D2 Antagonists on effort-related choice. However, less is known about the effects of adenosine A1 Antagonists. Despite anatomical data showing that A1 and D1 receptors are co-localized on the same striatal neurons, it is uncertain if A1 Antagonists can reverse the effects DA D1 Antagonists. The present work systematically compared the ability of adenosine A1 and A2A receptor Antagonists to reverse the effects of DA D1 and D2 Antagonists on a concurrent lever pressing/feeding choice task. With this procedure, rats can choose between responding on a fixed ratio 5 lever-pressing schedule for a highly preferred food (i.e. high carbohydrate pellets) vs. approaching and consuming a less preferred rodent chow. The D1 antagonist ecopipam (0.2 mg/kg i.p.) and the D2 antagonist eticlopride (0.08 mg/kg i.p.) altered choice behavior, reducing lever pressing and increasing lab chow intake. Co-administration of the adenosine A1 receptor Antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.375, 0.75, and 1.5 mg/kg i.p.), and 8-cyclopentyltheophylline (CPT; 3.0, 6.0, 12.0 mg/kg i.p.) failed to reverse the effects of either the D1 or D2 antagonist. In contrast, the adenosine A2A antagonist KW-6002 (0.125, 0.25 and 0.5 mg/kg i.p.) was able to produce a robust reversal of the effects of eticlopride, as well as a mild partial reversal of the effects of ecopipam. Adenosine A2A and DA D2 receptors interact to regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders.

  • substantia nigra pars reticulata is a highly potent site of action for the behavioral effects of the D1 antagonist sch 23390 in the rat
    Psychopharmacology, 2001
    Co-Authors: J T Trevitt, B B Carlson, K L Nowend, John D. Salamone
    Abstract:

    Rationale: Considerable evidence indicates that dopaminergic drugs, including drugs that act on D1 receptors, exert their effects by actions on forebrain dopamine terminal regions. Nevertheless, anatomical studies also have demonstrated that there is a high concentration of D1 receptors in the substantia nigra pars reticulata (SNr). The D1 receptors in SNr are located largely on the terminals of γ-aminobutyric acid (GABA)-ergic striatonigral neurons. The present studies were undertaken to determine whether the D1 antagonist SCH 23390 was effective if locally injected into SNr and to compare the results of SNr injections with those obtained from other brain sites. Fixed ratio 5 (FR5) lever pressing and open-field locomotion were used as the behavioral tests because these tasks are sensitive to systemic SCH 23390. Methods: Rats received bilateral implantations of guide cannulae into either nucleus accumbens, neostriatum, SNr, or control sites in the cortex or brainstem. Rats in the FR5 study were trained prior to surgery. All rats received one of the following local injections (0.5 µl per side): vehicle, 0.25, 0.5, 1.0, or 2.0 µg SCH 23390. Results: In the FR5 study, the SNr was by far the most potent site for suppression of lever pressing, with an ED50 (dose that produces half maximal response) of 0.33 µg per side. Nucleus accumbens and neostriatum injections were less potent than those in SNr, but more potent than injections into the control regions. With open-field locomotion, the SNr, nucleus accumbens, and neostriatum were approximately equipotent sites, and all three were more potent than the control sites. Conclusions: SNr was a very potent site for suppression of lever pressing and open-field locomotion. These data suggest that D1 Antagonists have multiple sites of action, including not only the forebrain dopamine terminal regions but also the SNr. It is possible that blockade of SNr D1 receptors modulates GABA release from striatonigral neurons.

John L Waddington - One of the best experts on this subject based on the ideXlab platform.

  • chapter 4 pre and postsynaptic D1 to d5 dopamine receptor mechanisms in relation to antipsychotic activity
    Antipsychotic Drugs and their Side-Effects, 1993
    Co-Authors: John L Waddington
    Abstract:

    Publisher Summary This chapter presents the initial presumptions on the role of D2 antagonism in antipsychotic activity, behavioral effects of selective D1 Antagonists in rodents, D1: D2 receptor interactions, antipsychotic potential and side-effects liability of selective D1 Antagonists, and the roles of D3, D4, D5 and other putative dopamine receptor subtypes. It is important to distinguish between the dopamine hypothesis of schizophrenia and the dopamine hypothesis of antipsychotic drug action. The latter proposes that reduction of dopaminergic function via either blockade of postsynaptic receptors or attenuation of presynaptic neuronal activity underlies the therapeutic effect of most known antipsychotic agents. Conversely, the former takes this concept a stage further and proposes that dopaminergic hyperfunction, via either super-sensitivity of postsynaptic receptors or elevated activity of pre-synaptic neuronal activity, is an important element in the patho-physiology of schizophrenia. The notions discussed in this chapter concern variants of the long-standing dopamine hypothesis of antipsychotic drug action, in terms of differing roles for distinct receptor subtypes in regulating dopamine-mediated function. In themselves, they do not yet demand any fundamental revision to the dopamine hypothesis of schizophrenia, pending more extensive feedback from clinical trials.

  • two directions of dopamine D1 d2 receptor interaction in studies of behavioural regulation a finding generic to four new selective dopamine D1 receptor Antagonists
    European Journal of Pharmacology, 1992
    Co-Authors: Siobhan A Daly, John L Waddington
    Abstract:

    A range of new, chemically distinct D1 dopamine receptor Antagonists, SCH 39166, NO 756, A-69024 and BW 737C, were studied for their effects on behavioural responses to the selective D2 agonist RU 24213. Each D1 antagonist not only blocked typical sniffing and locomotor responses to RU 24213 but also released atypical myoclonic jerking behaviour, while the selective D2 antagonist YM 09151 blocked these typical responses but did not release jerking. The rank order of effectiveness of these D1 Antagonists to release such D2 agonist-induced jerking was similar to that of their selectivities as D1 Antagonists; also, the action of BW 737C showed complete enantioselectivity, the inactivity of its R-antipode BW 736C paralleling enantioselective blockade of D1 but not D2 receptors. It appears that while tonic activity through D1 receptors is necessary for the expression of typical D2-stimulated behaviour, via well-known cooperative/synergistic D1:D2 interactions, D1 tone also normally inhibits, via oppositional D1:D2 interactions, the expression of atypical D2-stimulated behaviours such as jerking. Oppositional D1:D2 interactions are evident using all of the classes of selective D1 antagonist currently known, and appear to constitute another general mode of dopaminergic regulation.

Jean E Lachowicz - One of the best experts on this subject based on the ideXlab platform.

Carol Van Hartesveldt - One of the best experts on this subject based on the ideXlab platform.

Merle E Meyer - One of the best experts on this subject based on the ideXlab platform.